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6e7p

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cryo-EM structure of human TRPML1 with PI35P2

6e7p, resolution 3.50Å

Structural highlights

6e7p is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.5Å
Ligands:
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MCLN1_HUMAN Mucolipidosis type 4. The disease is caused by mutations affecting the gene represented in this entry.

Function

MCLN1_HUMAN Cation channel probably playing a role in the endocytic pathway and in the control of membrane trafficking of proteins and lipids. Could play a major role in Ca(2+) transport regulating lysosomal exocytosis.^[1] ^[2]

Publication Abstract from PubMed

Transient receptor potential mucolipin 1 (TRPML1), a lysosomal channel, maintains the low pH and calcium levels for lysosomal function. Several small molecules modulate TRPML1 activity. ML-SA1, a synthetic agonist, binds to the pore region and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P2, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P2 and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P2, PtdIns(4,5)P2, or ML-SA1 and PtdIns(3,5)P2, revealing a unique lipid-binding site. PtdIns(3,5)P2 and PtdIns(4,5)P2 bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P2 induces Y355 to form a pi-cation interaction with R403, moving the S4-S5 linker, thus allosterically activating the channel. Our structures and electrophysiological characterizations reveal an allosteric site and provide molecular insight into how lipids regulate TRP channels.

, PMID:30305615^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ LaPlante JM, Falardeau J, Sun M, Kanazirska M, Brown EM, Slaugenhaupt SA, Vassilev PM. Identification and characterization of the single channel function of human mucolipin-1 implicated in mucolipidosis type IV, a disorder affecting the lysosomal pathway. FEBS Lett. 2002 Dec 4;532(1-2):183-7. PMID:12459486
↑ Raychowdhury MK, Gonzalez-Perrett S, Montalbetti N, Timpanaro GA, Chasan B, Goldmann WH, Stahl S, Cooney A, Goldin E, Cantiello HF. Molecular pathophysiology of mucolipidosis type IV: pH dysregulation of the mucolipin-1 cation channel. Hum Mol Genet. 2004 Mar 15;13(6):617-27. Epub 2004 Jan 28. PMID:14749347 doi:http://dx.doi.org/10.1093/hmg/ddh067
↑ Fine M, Schmiege P, Li X. Structural basis for PtdInsP2-mediated human TRPML1 regulation. Nat Commun. 2018 Oct 10;9(1):4192. doi: 10.1038/s41467-018-06493-7. PMID:30305615 doi:http://dx.doi.org/10.1038/s41467-018-06493-7